专家简介
陈军 教授
天津医科大学总医院肺部肿瘤外科主任
博士，教授，主任医师，博士生导师
天津市肺癌研究所所长
天津市胸部肿瘤中心主任
天津市特聘教授，天津市津门英才
天津市“131”第一层次人选，教育新世纪优秀人才
中国老年保健协会肺癌专业委员会主任委员
中国医促会肺癌预防与控制分会副主任委员
中国微循环学会转化医学专业委员会副主任委员
欧美同学会-中国留学人员联谊会医师协会转化医学分会副主任委员
中国医促会胸外科分会常委
中国医师协会胸外科分会委员、中国抗癌学会肿瘤转移分会委员、中国抗癌学会肺癌专委会委员
《中国肺癌杂志》副主编，《Thoracic Cancer》编委
间质上皮细胞转化因子（MET）作为非小细胞肺癌（NSCLC）的关键驱动基因之一，其异常形式多样，包括MET 14外显子跳跃突变、MET扩增、MET蛋白过表达、MET融合及MET活化突变等。不同异常类型的分子特征、检测方法及治疗策略各有差异。近年来，随着对MET异常分子机制的深入研究和多款靶向药物的获批，针对这一靶点的临床诊疗策略日益清晰和精准。本文基于最新循证医学证据，对MET异常NSCLC的检测与治疗进行系统性梳理，旨在为临床实践提供参考。
1. MET异常的概述与流行病学
MET基因位于7号染色体，全长约125kb，包含21个外显子和20个内含子，其编码的蛋白c-Met为跨膜受体酪氨酸激酶，由胞外的SEMA、PSI、IPT1-4结构域和胞内的JM、TK、MDS结构域组成。当肝细胞生长因子（HGF）与c-Met结合后，会诱导c-Met二聚化及自身磷酸化，激活MAPK、PI3K/Akt、STAT3等下游通路，调控细胞增殖、迁移、侵袭及血管生成，其异常激活可通过多种机制驱动肿瘤发生发展[1-2]，主要包括：
1.1 MET 14外显子跳跃突变（MET ex14跳跃突变）
MET ex14跳跃突变是MET异常中最经典的激活形式之一，该突变会导致MET蛋白JM结构域缺失，进而引发MET蛋白无法与泛素化蛋白结合，影响MET蛋白的正常降解，进而持续激活下游通路，促进肿瘤的发生发展[3]。MET ex14跳跃突变在中国人群中的发生率为0.9%-2.0%[4-9]，不同病理类型上，MET ex14跳跃突变在肺腺癌中发生率约为3%[10]，肺鳞癌为1%-2%[11-12]，肺肉瘤样癌中可达13%-22%，且多见于老年患者[13-16]。此类患者肿瘤侵袭性强，对传统化疗及免疫治疗反应不佳[8,17-21]。
1.2 MET扩增
MET扩增是指MET基因在肿瘤细胞中的拷贝数异常增加。原发性MET扩增在NSCLC中发生率较低（1%-5%）[17]，但它是EGFR-TKIs耐药的重要机制。在一/二代EGFR-TKI耐药后发生率为5%-22%[22-23]，第三代EGFR-TKI奥希替尼耐药后发生率为5%-50%[24]。它也是ALK-TKIs的耐药机制之一[25]。
1.3 MET蛋白过表达
MET蛋白过表达可由MET基因扩增、转录上调、缺氧、炎症因子等多种因素引起[26]。其在NSCLC中的发生率报道差异较大，中国人群为17.5%-63.7%[27-29]。在EGFR-TKI经治的EGFR突变患者中，发生率约为30.4%-37.0%，EGFR野生型MET蛋白过表达的发生率约为44.4%[30-31]。随着靶向MET的抗体药物偶联物（ADC）问世，其临床意义日益凸显。
1.4 其他类型
包括MET基因融合（发生率0.26%-0.5%）和激酶区点突变等，虽较为罕见，但同样是潜在的治疗靶点[32]。
2. MET异常的检测
准确检测MET异常是实施精准治疗的前提。当前国内外主要指南（如NCCN、CSCO等）均推荐对晚期NSCLC患者进行MET异常检测[33-34]。
检测必要性：MET ex14跳跃突变已成为晚期NSCLC的必检项目。同时，鉴于MET扩增及过表达在原发性驱动和EGFR-TKI耐药中的关键作用，以及相关靶向药物（包括MET-TKI和MET-ADC）的获批，推荐对初治及EGFR-TKI耐药患者常规进行MET扩增和蛋白过表达检测[33-37,43]。
检测方法：
2.1 MET ex14跳跃突变检测
推荐使用实时定量PCR（RT-qPCR）、DNA二代测序（NGS）或RNA NGS进行检测。DNA-NGS通量高，但需确保探针覆盖关键区域；RNA-NGS可直接检测异常剪接的mRNA，可能具有更高灵敏度，但需优质样本。临床中可根据条件选择或互补验证。
2.2 MET基因扩增检测
荧光原位杂交（FISH）是检测的金标准。常用Cappuzzo标准（GCN≥5）或UCCC标准（MET/CEP7比值≥2.0）进行判读。DNA-NGS检测与FISH的一致性正在提高，但其作为独立检测标准仍需进一步验证。如客观条件不支持进行二次活检的患者可使用液体活检作为补充[17,44-47]。
2.3 MET蛋白过表达检测
免疫组织化学（IHC）是标准检测方法。检测结果的标准化判读至关重要，目前普遍采用“Clinical Score”判读标准，即结合染色强度和阳性肿瘤细胞比例进行综合评分。多项关键临床研究将“≥50%的肿瘤细胞呈现中至强染色（2+/3+）”作为潜在获益的阈值。美国FDA已批准VENTANA MET（SP44）检测作为伴随诊断，其定义的“高表达”即为≥50%肿瘤细胞强染色[38,48,49]。
3. MET异常NSCLC的治疗进展
3.1 MET ex14跳跃突变的治疗
目前，已有5款高选择性MET-TKI在国内获批用于治疗携带MET ex14跳跃突变的局部晚期或转移性NSCLC患者，显著改善了患者预后（表1）[20,50-56]。
赛沃替尼治疗MET ex14跳跃突变的NSCLC的IIIb期临床研究报道的初治人群ORR为62.1%，中位缓解持续时间（duration of remission, DOR）为12.5个月，中位PFS为13.7个月，中位OS为28.3个月；经治人群ORR为39.2%，中位DOR为11.1个月，中位PFS为11个月，中位OS为25.3个月。
谷美替尼GLORY研究是一项单臂、多中心、II期研究，评估了谷美替尼治疗MET ex14跳跃突变的局部晚期或转移性NSCLC的有效性和安全性。总体受试者的ORR为66%，其中初治患者与既往经治患者的ORR分别为71%和60%；中位PFS为8.5个月，其中初治患者为11.7个月，既往经治患者为7.6个月；中位OS为19.4个月，其中初治患者为25.4个月，既往经治患者为16.3个月；基线有脑转移的13例患者中，ORR为85%（11/13），其中5例患者的脑转移病灶被选为靶病灶并在治疗后测量，该5例患者均观察到颅内PR，颅内ORR为100%。
伯瑞替尼KUNPENG研究是一项针对局部晚期或转移性MET异常的NSCLC患者的II期研究，MET外显子14跳突队列共纳入52例NSCLC患者，经BIRC评估的总体ORR为75.0%，疾病控制率（disease control rate, DCR）为96.2%，中位DOR为16.5个月，中位PFS为14.3个月，中位OS为20.3个月，3年OS率为35.1%。亚组分析显示，初治患者ORR为77.1%，既往经治患者ORR为70.6%。
特泊替尼VISION研究显示，总体患者人群中的ORR为51.4%，中位DOR为18个月，中位PFS为11.2个月，中位OS为19.6个月。
卡马替尼GEOMETRY mono-1研究结果显示，在初治患者队列中ORR为68%，中位DOR为16.6个月，中位PFS为12.5个月，中位OS为21.4个月；既往经治患者的ORR为44%，中位DOR为9.7个月，中位PFS为5.5个月，中位OS为16.8个月。
此外，也有研究积极探索非TKIs类药物治疗MET 14跳突NSCLC的效果。埃万妥单抗CHRYSALIS[57] I期研究中，MET ex14队列的总ORR为33%，中位DOR为11.2个月。
3.2 MET扩增的治疗
MET扩增的治疗需区分原发性扩增与EGFR-TKI耐药后继发性扩增。
3.2.1 原发性MET扩增：现有临床研究数据（表2）提示MET-TKIs可能为此类患者带来获益[56-60]。伯瑞替尼在KUNPENG研究的扩增队列中显示出前景，在MET基因拷贝数≥6的患者中，总体ORR为48.8%，中位PFS为7.4个月，并基于此数据获NMPA附条件批准用于治疗MET扩增NSCLC。卡马替尼的研究提示，其疗效与扩增程度相关，在高水平扩增（基因拷贝数≥10）的患者中观察到更好的缓解率。
3.2.2 EGFR-TKI耐药后继发性MET扩增：是当前临床实践中的常见且重要场景。采用EGFR-TKI联合MET-TKI的双靶向策略，可有效克服EGFR-TKI耐药后旁路激活（表3）[36-42,61,65-66]。
赛沃替尼联合奥希替尼：SAVANNAH研究揭示，疗效与MET扩增/过表达水平密切相关。在MET高水平扩增或过表达（GCN≥10和/或IHC 90% 3+）的患者亚组中，联合治疗的ORR达49%，中位PFS为7.1个月；而在低水平（非GCN≥10和/或IHC 90% 3+）患者中获益有限，ORR仅9%，中位PFS为2.8个月。随后的III期SACHI研究评估了该联合方案对比化疗用于晚期NSCLC一线EGFR-TKI进展后伴MET扩增（一/二代EGFR-TKI经治：FISH检测MET GCN≥5或MET/CEP7≥2.0，且T790M阴性；三代EGFR-TKI经治：MET GCN≥10）的疗效和安全性，结果显示，联合组在ORR、DCR方面均显著优于化疗组，且能够延长患者的PFS。基于此数据，赛沃替尼获NMPA批准用于EGFR基因突变阳性，经EGFR-TKI治疗后进展的伴MET扩增的局部晚期或转移性非鳞状NSCLC患者。
谷美替尼联合奥希替尼：SCC244-203研究评估了谷美替尼联合奥希替尼治疗第一、二、三代EGFR-TKIs耐药后MET扩增NSCLC患者的有效性和安全性。在整体人群中，ORR达到60%，DCR达到90%，中位PFS达6.9个月，中位OS达16.9个月。
特泊替尼联合吉非替尼：INSIGHT研究结果显示，与化疗相比，联合组改善了EGFR-TKIs耐药后MET扩增NSCLC患者的PFS、OS、ORR和DOR：特泊替尼联合吉非替尼组和化疗组的中位PFS分别为16.6和4.2个月（HR=0.13），中位OS分别为37.3和13.1个月（HR=0.10），ORR分别为66.7%和42.9%，中位DOR分别为19.9和2.8个月。
特泊替尼联合奥希替尼：INSIGHT 2的主要分析[41]显示，在伴有MET扩增且一线奥希替尼进展的EGFR突变NSCLC患者中，特泊替尼联合奥希替尼治疗的ORR为50%，中位DOR为8.5个月。
卡马替尼联合吉非替尼：一项Ib/II期研究评估了卡马替尼联合吉非替尼治疗EGFR-TKIs治疗失败并伴有MET扩增/过表达的NSCLC患者的有效性和安全性。II期研究的ORR为27%，中位DOR为5.6个月。在高MET扩增肿瘤的患者中，MET活性增加，MET基因GCN≥6的患者的II期ORR为47%。
伯瑞替尼联合PLB1004：KYLIN-1是一项Ib/II期研究，旨在评估伯瑞替尼联合PLB1004（安达艾替尼）治疗EGFR-TKIs耐药后伴MET扩增/过表达NSCLC患者的有效性和安全性。该研究在RP2D剂量下共入组56例患者，确认的ORR为50.0%。DCR为89.3%，mPFS为9.9个月。经一代/二代EGFR-TKI治疗后进展患者，DCR为87.8%，经三代EGFR-TKI治疗后进展患者，DCR为89.5%，mPFS为9.6个月。
也有研究积极探索非TKIs类药物治疗MET扩增NSCLC的效果。REGN5093是一种新型的双特异性抗体药物，同时靶向MET和EGFR。一项I/II期研究评估了REGN5093单药治疗MET异常晚期NSCLC患者的有效性，研究发现，MET扩增患者队列的ORR为25%。
3.3 MET蛋白过表达的治疗
MET蛋白过表达的治疗根据其背景分为两类：
EGFR-TKI耐药后MET蛋白过表达：研究提示，IHC检测为高表达（如≥50%肿瘤细胞强染色3+）的患者可能从EGFR/MET双靶联合中获益。INSIGHT、TATTON等研究为此提供了依据[48,49]。此外，MET-ADC药物Telisotuzumab vedotin（Teliso-V）联合厄洛替尼在经治患者中显示出抗肿瘤活性，尤其在MET高表达亚组。埃万妥单抗联合拉泽替尼在奥希替尼耐药、EGFR/MET高表达的NSCLC中也展现出潜在获益[68]。
驱动基因阴性MET蛋白过表达：对于不伴有其他明确驱动基因的MET过表达NSCLC，治疗选择正在拓展。谷美替尼单药在此类患者中ORR为37.5%，中位OS为17个月[62]；其联合化疗的研究也显示出积极信号：在驱动基因阴性的MET蛋白表达2+或3+（IHC≥50% 2+且＜50% 3+或IHC ≥50% 3+）二线患者中，联合方案的整体ORR为 34.8%，其中IHC 3+亚组为60%，DCR在整体、IHC 3+和IHC 2+亚组分别为95.7%、100%和94.4%[69]。LUMINOSITY研究则证实了Teliso-V单药在EGFR野生型、MET高表达非鳞NSCLC二线治疗中的疗效，并基于此获FDA加速批准，用于治疗经治的EGFR野生型、MET高表达（IHC 3+≥50%）非鳞状NSCLC患者[70]。但Teliso-V目前还未在国内获批上市。
4. 未来展望
尽管MET异常NSCLC治疗取得了长足进步，但未来仍面临诸多挑战与机遇。
检测标准化：统一MET扩增的NGS判读标准、优化MET蛋白IHC的检测与判读阈值，是确保精准治疗的前提。液体活检（如ctDNA）在动态监测耐药中的应用值得深化。未来可能需结合多种生物标志物（如MET蛋白表达、特定突变等）进行综合评估，以实现更精准的疗效预测。
优化现有治疗与克服耐药：对于MET扩增，需要更多III期研究确立标准治疗方案，并探索MET-TKIs与其他靶向药的联合策略。此外，克服MET-TKIs的获得性耐药是关键挑战，耐药机制包括靶点依赖性突变（如MET TKD突变D1228N/Y1248H等）和旁路激活。探索针对这些耐药突变的新一代药物，或采用ADC、双特异性抗体等不同作用机制的药物，是未来的研究方向。
拓展MET过表达治疗适应症：MET-ADC（如Teliso-V）的FDA获批以及谷美替尼数据的公布为驱动基因阴性MET蛋白过表达患者提供了新选择。未来还需要更大规模的II和III期临床试验来进一步验证疗效和安全性。
探索罕见MET异常及新治疗场景：对于MET融合、KDD（激酶结构域复制）等罕见异常，需积累更多临床数据明确其最佳治疗策略[71-73]。此外，MET-TKIs在可手术早期NSCLC中的辅助或新辅助治疗价值，正在多项临床试验中进行探索，初步的个案报告[74-77]显示了其诱导肿瘤缩小的潜力，有望为早期患者带来新获益。
总结
当前，MET异常NSCLC的诊疗已进入分子分型指导下的精准时代。在治疗上，针对MET ex14跳跃突变，多种高效MET-TKI可供选择；针对MET扩增，靶向治疗已成为标准策略；而对于MET蛋白过表达，MET-TKI和ADC药物治疗有了新的突破。未来，通过检测技术的标准化、治疗策略的优化、耐药机制的攻克以及治疗前移的探索，有望为更多MET异常NSCLC患者带来生存获益。
【参考文献】
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编辑：Lagertha
审核：陈军教授
来源：肿瘤界
